Prolidase-dependent regulation of TGF c and TGF β receptor expressions in human skin fibroblasts

Transforming growth factor beta 1 (TGF beta 1) is a protein that in most cells control proliferation and differentiation One of the best characterized functions of TGF beta 1 is stimulation of collagen biosynthesis that may lead to tissue fibrosis Several reports suggest that prolidase through regulation of expression of growth factors and transcription factors e g vascular endothelial growth factor (VEGF) and hypoxia-inducible factor la (HIF 1 alpha) may be important in many physiologic and pathophysiologic processes like wound healing inflammation and angiogenesis We found that inhibitors of prolidase activity (N benzyloxycarbonyl-L proline Cbz-Pro and phosphoenolopyruvate PEP) induced decrease in TGF beta 1 and its receptor expressions On the other hand products of prolidase catalytic activity proline (Pro) and hydroxyproline (HyPro) induced Increase in the amount of TGF beta 1 and TGF beta receptors Simultaneously inhibitors of prolidase induced down-regulation of expression of the phospho-AKT An addition of Pro or HyPro to the cells induced Increase in the expression of phospho-AKT An important transcription factor involved in signal induced by TGF beta receptor is mammalian target of rapamycin (mTOR) We found that prolidase inhibitors induced decrease in the expression of phospho-mTOR. while Pro or HyPro counteracted the effect Rapamycin (pharmacological inhibitor of mTOR) resulted in decrease in prolidase activity The down-regulation of phospho-mTOR by rapamycin contributed to down regulation of prolidase activity suggesting its important role in prolidase dependent function It seems that products of prolidase activity Pro or HyPro may act as an interface between mTOR and phospho-mTOR in regulation of numerous TGF beta receptor dependent functions (C) 2010 Elsevier B V All rights reserved